The field of the present invention is the synthesis of optically active compounds. A highly stereospecific process for synthesis of paroxetine is described herein.
Paroxetine is a compound widely used for the treatment of depression. The structural formula of this compound is as follows (I): 
The molecule of formula (I) contains two chiral centres on the piperidinic ring, in position 3 and 4, respectively. Of the four possible isomers, only the isomer having absolute configuration 3S, 4R, known as 4R-trans-4-(p-fluorophenyl-3-{[3,4-(methylenedioxy)phenoxy]methyl}piperidine, is pharmacologically active. Therefore, the processes for synthesis of paroxetine must result in the formation of the 4-(p-fluorophenyl-3-{[3,4-(methylenedioxy)phenoxy]methyl}piperidinic structure, exclusively in the aforesaid conformation, 3S, 4R (or 4R-trans).
Some processes for synthesis of paroxetine known to the art are based on the formation of an intermediate of formula (II) 
where R represents an alkyl group. Starting from this intermediate, the product of formula (I) is obtained by: (i) reduction of the piperidinic double bond, (ii) alkylation of the oxygen of the hydroxymethyl group, and (iii) removal of the alkyl group R bound to the nitrogen. In order to obtain the product (I) with the pharmacologically active conformation, the process requires the isolation of specific isomers from the corresponding racemic mixtures and the treatment of the same until obtaining derivative (I) with the desired conformation.
For example, patent application WO-A-9636636 discloses the synthesis of 4-arylpiperidine, wherein a derivative of formula (II) is separated into the two optical isomers by crystallisation with optically active salts. The two optical isomers are then separately converted into paroxetine. Therefore, the process requires separate and independent synthesis routes for isomers treatment and, consequently, can hardly be scaled up to commercial size.
According to another process (J. Labelled Compounds Radiopharm., 1993, 8, 785), the derivative of formula (II) is hydrogenated and alkylated as per the above scheme; subsequently the diastereoisomers are isolated by chromatography while the enantiomers are separated by crystallisation with L-(+)-tartaric acid. The (xe2x88x92)-trans isomer is finally converted into paroxetine by N-dealkylation. In this case, two distinct isomers separation cycles are required, resulting in a considerable loss of product in the form of undesired isomer. Consequently, this process too can hardly be applied to commercial-scale production.
The process disclosed in patent application WO-A-9322284 is based on the stereospecificity of esterase-catalysed reactions. In this case, the enzyme brings about the formation of a trans carboxylic precursor, wherefrom the (+)-trans and (xe2x88x92)-trans forms are separated by conventional methods. The latter form further undergoes reduction and alkylation to give paroxetine. The advantage of this process is a high stereospecificity; its disadvantages are the enzyme cost and instability. The aforesaid reactions are usually slow and must be carried out under precise pH and temperature conditions.
In brief, the separation processes known to the art cause a considerable loss of product in the form of isomers with undesired configuration or require separate process cycles for the conversion of said isomers. In particular, the processes known to the art entail the resolution of racemic mixtures in which the dextro- and levorotatory components are present in substantially similar proportions, with the result that approx. half of the resolved product is to be discarded or independently converted into the desired form.
Therefore, the need for developing highly stereospecific processes for the synthesis of paroxetine, whereby the desired isomers are obtained in high yields, is felt. Particularly urgent is the need for processes not involving isomer resolution cycles and not requiring separate ad hoc treatments of the single isomers.